A significant issue for the remediation of facial pain is the modulation of glutamate release from orofacial afferents in the trigeminal nucleus caudalis (Vc). Although the postsynaptic effects of glutamate are partly mediated by ionotropic glutamate receptors in the Vc, it is unknown whether kainate or metabotropic glutamate receptors modulate pain transmission. The basic working hypothesis is that different populations of trigeminal afferents in the Vc contain different combinations of pre- and postsynaptic receptors, leading to differential modulation of pain transmission. The project will use electron microscopic immunocytochemistry to examine the distribution of kainate, metabotropic and /z-opiate receptors (MORs) in the synapses made by identified trigeminal afferents in the Vc. The synaptic organization of two populations of corneal afferents will be a focus of the research, and they will be identified with tract tracing; other Vc afferents will be identified using neurochemical markers of nociception. There are 4 aims. Aim 1 will determine if kainate receptors are located in primary afferent terminals where they may modulate presynaptic transmitter release. Aim 2 will determine whether the distribution of metabotropic glutamate receptors is different among the two corneal afferent systems to the Vc and among afferents that contain substance P. Aim 3 will determine if MORs are located at sites postsynaptic to axon terminals of corneal afferents and to those that contain the endogenous opioid endomorphin-2, which would be expected if this peptide is an endogenous ligand for the MOR. Aim 4 will determine if MORs are found in corneal afferents and those that contain VR1, which identifies a distinct population of thermal nociceptive afferents. Together the studies will determine the subcellular localization of glutamate receptors and MORs in trigeminal pathways that may be targets for new therapeutic strategies to control trigeminal pain.